Aligned with previous studies, transfecting FKN into cardiomyocytes, fibroblasts, and endothelial cells, led to increased expression of ANP, ICAM-1, MMP-9, TGF-β, procollagens I and III in cells in vitro while treating with RES reversed all these results.

Exposing neonatal rat cardiomyocytes to RES led to increased autophagosomes and overexpression of LC3-II and Atg5 proteins participate in autophagy while treating these cells with FKN reversed the effects of RES, indicating contrary effects of FKN on HF.

This study suggests that RES collectively improves HF conditions and complications by antagonizing the effects of FKT Moreover, the expression of collagen-I and -III and TGF-β cardiac fibrosis factors decreased after RES treatment, and the expression of phosphorylated eNOS a marker for cardiac stiffness was increased after treatment with RES, indicating that RES reduces cardiac fibrosis and stiffness Silent information regulator 1 SIRT1 is a class III histone deacetylase that protects the cardiovascular system against oxidative stress by boosting antioxidant defense and inhibiting apoptosis, inflammation, and autophagy — RES is an activator of SIRT1, which exerts cardioprotective effects by enhancing its expression.

Sirt1 is a primary regulator of cell metabolism, and recent studies revealed its role in oxidative stress and fibrosis , Previous studies have shown that increased activity of Sirt1 reduces cardiac fibrosis by negatively targeting Smad3 and decreasing its acetylation and transcription , , Autophagy and apoptosis are two crucial CH processes , Guan et al.

These subunits are associated with cardiac disorders , A study by Chen et al. In this study, RES treatment significantly alleviated cardiac hypertrophy and dysfunction.

Treating Ang II-induced cardiomyocytes in-vitro with RES also decreased proteasome caspase-like, trypsin-like, and chymotrypsin-like activities, increased expression of PTEN, and decreased expression of cardiomyocyte size Oxidative stress inhibits LKB1 activity, leading to AMPK suppression AMPK improves vascular function by activating endothelial NO synthase eNOS and producing nitric oxide NO , In this light, RES was found to activate AMPK by enhancing the expression of LKB1, leading to increase NO production and improved vascular function.

Indeed, Dolinsky et al. Consistent with this study, Thandapilly et al. reported that RES 2. Inflammation, oxidative stress, and coronary artery endothelial dysfunction are essential in developing cardiac fibrosis In a study by Zhang et al.

Functionally, RES suppressed cardiac inflammatory response by downregulating IL-1β, IL-6, and TNF-α and reducing inflammatory cell infiltration in cardiac tissue Based on IL production by macrophages involved in inducing myocardial fibrosis , the role of RES on cardiac macrophage activity was investigated.

They found that the expression of M1 markers increased in the HF group. However, treatment with RES shifted macrophage polarization to the M2 phenotype, which has tissue repair effects Atorvastatin is a lipid-lowering drug with anti-inflammatory, antioxidant, and antiproliferative properties , Besides lowering cholesterol levels, atorvastatin has many beneficial effects on the cardiovascular system Chakraborty et al.

CH is the pathological growth of the heart due to pressure or volume overload, loss of contractibility, chemical toxicity, and congenital disorders CH is a beneficial adaptive response that removes the effect of extrinsic or intrinsic stress to preserve cardiac function.

However, excessive CH is deleterious and leads to adverse complications such as HF RES suppresses CH by regulating diverse signaling pathways in cardiomyocytes.

NFAT is a transcriptional factor that activates GATA4, which induces cell hypertrophy The benefits of calcineurin inhibitors have been shown in terms of preventing CH The study by Chan et al.

Further examination revealed that RES inhibited CH processes by activating AMP-AMPK through upregulating liver kinase B1 LKB1 , the activating kinase of AMPK, leading to inhibition of p70S6K, eEF2, and NFAT signaling pathways Also, AMPK could inhibit CH through NFAT, NF-κB, and MAPK signal pathways RES could exert beneficial effects by regulating micro RNAs miRNAs , a central subgroup of non-coding RNAs, as an alternative molecular mechanism.

Fan et al. They showed that miR induces cardiomyocyte hypertrophy and disrupts cardiac function BRCA-1 is an essential gene for heart development and exerts cardioprotective effects in adult hearts Angiotensin II is one of the renin-angiotensin system hormones with a vital role in the progression and development of several CVDs, such as hypertension, CH, and HF Mashhadi et al.

showed that expression of AT1a Ang receptor was increased in the hypertrophic rat heart, indicating that the Ang receptor plays a vital role in the development of PO-induced cell hypertrophy.

Exercise intolerance is an essential feature of chronic HF, and identifying its underlying mechanism may help improve the quality of life of patients with HF Recent studies have shown that impaired skeletal muscle function, structure, and metabolism play an important role in exercise intolerance in HF patients In this way, some studies have shown that RES can improve rodents' skeletal muscle biogenesis, isometric force, and metabolism , Sung et al.

A significant improvement in HF mice's respiratory exchange ratio RER was observed. Decreased RER in HF mice indicates more use of fatty acids than glucose in metabolism, producing more ROS and increasing oxidative stress.

Treatment with RES elevated RER level, indicating that substrate utilization in the metabolic cycle shifted towards glucose; also, the total metabolic rate was increased after RES treatment Mechanistically, RES treatment increased phosphorylation and expression of IRS-1, Akt, and AMPKα, which were reduced in HF and enhanced insulin sensitivity of skeletal muscles.

This study also indicated that RES improved metabolism and insulin resistance in HF mice by altering the gut microbial community, which is associated with systemic metabolic rate and insulin sensitivity. showed that RES enhanced the cecum bacterial profile, increasing glucose homeostasis and carbohydrate metabolism Curcumin [ 1E,6E -1,7-bis 4-hydroxymethoxyphenyl hepta-1,6-diene-3,5-dione] is a natural polyphenol substance extracted from turmeric that plays substantial roles in cellular function by regulating various signaling pathway.

Curcumin benefits various pathologic conditions and has anti-inflammatory and antioxidant effects According to these features, curcumin can be used as a therapeutic element in various diseases Several studies have reported the positive role of curcumin in attenuating CVDs, such as atherosclerosis, MI, and HF , Tang et al.

The results demonstrated the ameliorating of curcumin's role in cardiac remodeling and HF's diastolic dysfunction. Also, curcumin significantly reduced collagen deposition in heart tissue Table 1. The p, a histone acetyltransferase HAT enzyme, regulates the expression of multiple genes by chromatin remodeling.

P can also coactivate other transcriptional factors, such as GATA4 , , a member of the zinc-finger transcription factor family with high expression in cardiomyocytes and plays a critical role in cardiomyocyte differentiation GATA4 regulates the transcription of ANP, α- and β-myosin heavy chain α-MHC and β-MHC , which play a role in cardiac remodeling Therefore, it seems that overexpression of p induces cardiac remodeling by increasing the activation of GATA4 Several studies have reported curcumin as a natural pspecific HAT inhibitor that can improve cardiac remodeling in HF.

Morimoto et al. Mechanistically, curcumin reduced GATA4 and p binding but did not change their expression. Dickkopf-related protein 3 DKK-3 , a member of dickkopf glycoprotein, regulates cell proliferation.

Also, DKK-3 could modulate the immune system by acting as a cytokine-like protein , DDK-3 is involved in cardiac remodeling and vascular smooth muscle differentiation, and several studies demonstrated the cardioprotective effects of DDK-3 Zhang et al. showed that suppressing the expression of DDK-3 increases cardiac dysfunction and remodeling while augmenting the expression of DDK-3 improves cardiac function in an animal model of HFrEF Moreover, DDK-3 improves chronic HF conditions by suppressing c-Jun N-terminal kinase JNK signaling pathways by inhibiting p38 mitogen-activated protein kinase p38 It has been found that P38 and JNK signaling pathways are highly activated in HF and participate in cardiac remodeling , In addition, expression of DDK-3 increased in curcumin-treated mice, compared with untreated mice with HF.

Liu et al. studied the effects of curcumin on isoproterenol ISO -induced CH and the molecular mechanism behind it. It has been found that the mTOR signaling pathway exerted cardioprotective effects by decreasing autophagy Consistent with these studies, Bai et al.

Treatment with NCX inhibitor KB-R reversed the protective effects of curcumin on the myocardium and vessels. These results indicate that curcumin exerts cardioprotective effects by upregulating NCX expression in response to increased afterload Quercetin QCT is a natural flavonoid polyphenol widely found in fruits and vegetables such as onions, peppers, plums, mangos, and berries and is a potent anti-inflammatory, antioxidant, and anti-cancer component — Quercetin regulates several molecular pathways in cellular processes and exerts many beneficial effects on the cardiovascular system, such as anti-hypertensive and cardioprotective effects, by suppressing inflammation, oxidative stress, and apoptosis in the heart , Several studies investigated the mechanisms behind the cardioprotective effects of QCT.

showed that QCT inhibits the NF-κB pathway by activating peroxisome proliferator-activated receptor-γ PPARγ protein and preventing cardiac damage For further investigation, Chang et al. administered QCT to improve cardiac function and hypertrophy in rats with TAC-induced HF.

QCT decreased cardiac fibrosis by modulating TGF-β and MMPs, inflammatory cytokines TNF-α, IL, IL , and production of ROS by activating the expression of SIRT5 and IDH2 desuccinylation. Succinylation regulates mitochondrial metabolism and function; impaired succinylation and mitochondrial function lead to oxidative stress and inflammation.

This study showed that QCT regulates mitochondrial energy metabolism and improves oxidative stress by increasing succinylation through increasing expression of SIRT5 Anti-hypertrophic properties of quercetin have been reported in several studies — QCT can prevent cardiac remodeling in mice.

Wang et al. Also, quercetin attenuated ventricular wall thickness in mice, indicating the anti-hypertrophic effects of QCT SIRT3 is a type III histone deacetylase with anti-hypertrophic effects on the heart The expression of SIRT3 was increased by QCT, indicating that the anti-hypertrophic effects of QCT are related to the SIRT3-mediated signaling pathways.

PARP-1 is an up-regulated enzyme in hypertrophic hearts, and overexpression of SIRT3 inhibits its function Moreover, In vitro investigation showed that treating Ang II-induced H9c2 cells with QCT prevents hypertrophic response, restores impaired mitochondrial structure and function, reduces ROS generation, and decreases oxidative stress Oxidative stress and ROS play essential roles in the development of CH.

In this study, QCT treatment restored endogenous antioxidant enzyme CAT and SOD activity, increased sulfhydryl protein levels, and decreased H 2 O 2 a major ROS. Altogether this study revealed that QCT attenuates pre-existing CH by balancing oxidation and protecting mitochondria QCT also reduced oxidative stress in the heart tissue of AAC rats.

This study showed that rats with a QCT-supplemented diet have lower blood pressure and CH in pressure-overload stress conditions Table 1.

Gallic acid 3, 4, 5-trihydroxy benzoic acid is a polyphenol component in green tea, blackberry, grapes, wine, mangoes, and walnuts. It can be an anti-cancer, anti-allergic, anti-microbial, antioxidant, and anti-inflammatory factor , Gallic acid GA impacts the cardiovascular system, such as attenuating cardiac fibrosis, hypertension, oxidative stress, and eventually HF.

The antioxidative effects of gallic acid suppress cardiac hypertrophy and protect cardiomyocytes against damage , , An in vitro investigation conducted by Yan et al. In this experiment, GA increased cardiomyocyte autophagy by inhibiting ULK1 phosphorylation autophagy regulator , which leads to the degradation of unnecessary products and improved cardiac remodeling.

GA decreased inflammatory markers, myocardial superoxide products, and fibrosis factors in the heart of mice with HF. Collectively, GA exerts its cardioprotective effects and improves cardiac remodeling by activating autophagy through various pathways The levels of HF markers, such as ANP, BNP, and β-MHC, significantly decreased after GA treatment.

Pulmonary fibrosis is a severe complication of HF due to increased left atrial pressure, pulmonary edema, and fibrosis formation According to the anti-fibrotic effects of gallic acid in other studies, Jin et al. Expression of epithelial-mesenchymal transition EMT markers, including N-cadherin and SNAI1, was increased in the TAC group, and treatment with GA reduced their expression, suggesting the inhibitory role of GA in HF-induced pulmonary fibrosis by inhibiting the EMT process EMT participates in tissue repair and induces pulmonary fibrosis According to the well-established effects of GA on CVDs, Jin et al.

investigated mechanisms of GA affecting blood pressure and CH. Arterial remodeling and vascular contractibility were also reduced by GA treatment, indicating the regulatory effect of GA on vascular smooth muscle. Collectively, GA alleviated hypertension and CH by suppressing Nox2 activity and Nox2-induced oxidative stress via inhibiting GATA4 expression Additionally, GA prevented ISO-induced CH and improved cardiac dysfunction by decreasing the expression of hypertrophy-related and fibrosis-related genes.

To investigate the role of JNK2 in cardiac fibrosis and hypertrophy, they transfected JNK2 into cardiomyocytes which led to increased Smad3 and collagen type I protein levels, inducing cell hypertrophy and fibrosis. Consequently, this study showed that GA prevents ISO-induced cardiac hypertrophy by regulating JNK2 signaling and Smad3 binding activity Table 1.

Estrogen has shown an influential role in protecting the cardiovascular system, especially in improving the pulmonary and cardiac function of pulmonary hypertension PH cases, by binding to estrogen receptor-β ERβ , Genistein, an isoflavone derived from soybean, functions as a natural estrogen, can bind to ERβ stronger than estrogen, and can exert anti-inflammatory and anti-cancer effects — According to the unwanted side effects of estrogen as a drug, genistein can be used instead of the pharmacological form of estrogen.

Also, several studies have shown that genistein intake can ameliorate cardiovascular risk factors such as hypertension and lipid profile Matori et al.

This study confirms the beneficial cardiopulmonary effects of genistein in rats with PH Genistein has shown anti-hypertrophic effects in several studies. Meng et al. Nitric oxide synthases NOS catalyze NO production from L-arginine.

Neuronal nitric oxide synthase nNOS and endothelial nitric oxide synthase eNOS have anti-hypertrophic effects on the heart, but inducible nitric oxide synthase iNOS induces hypertrophy Maulik et al.

investigated the effects of genistein 0. Genistein exerts anti-hypertrophic effects via eNOS, nNOS, and antioxidant effects in ISO-induced CH rat models Recent studies have shown that genistein exerts parts of its effects by regulating the expression of miRNAs Gan et al.

Expression of the TIMP2 gene was increased in the ISO-induced CH heart, indicating pro-hypertrophic effects of TIMP2 Table 1. Pterostilbene [4- 3,5dimethoxystyryl phenol] is a polyphenol structurally similar to RES and has potential pharmacological impacts such as anti-cancer, anti-inflammatory, antioxidant, and anti-apoptosis — Furthermore, Lacerda et al.

Enhancing the glutathione redox cycle was suggested as an underlying mechanism of the antioxidative effects of PTS The glutathione redox cycle protects the cell membrane from LPO and oxidative stress Phospholamban is a protein that regulates calcium channels in the heart, and SERCA is a calcium transporter in the cell.

Both these proteins play a significant role in calcium transportation and cardiac muscle contractility , Table 1.

Kaempferol can protect cells against oxidative stress and inflammation and exerts various pharmacological effects such as anti-microbial, anti-diabetic, and anti-cancer Kaempferol exerts pleiotropic beneficial effects on the cardiovascular system, including ameliorating cardiac fibrosis, preventing HF, improving myocardial damage repair, and decreasing atherosclerosis , , Zhou et al.

Diabetes is one of the significant risk factors for HF development ; thus, according to the positive effects of KF on both the cardiovascular system and diabetes, Zhang et al.

Results of this study demonstrated that treatment with KF exerts significant cardioprotective effects in diabetic rats as it suppresses inflammation, oxidative stress, and apoptosis and alleviates blood glucose levels and serum cardiac markers Regarding the underlying mechanism, KF modulated the nuclear factor erythroid 2-related factor 2 Nrf2 signaling pathway, which protects cells against ROS, and the nuclear factor-light-chain-enhancer of activated B cells NF-κβ signaling pathway, which has a vital role in fibrosis.

The activity of antioxidant enzymes was increased, while the LPO level was decreased after treatment with KF. Expression of inflammatory factors, including NF-κβ p65, TNF-α, IL-6, IL-1β, p-IKKβ, and COX-2, significantly decreased. Cardiac apoptosis markers caspase-3 and Bax were decreased, while the anti-apoptotic marker Bcl-2 was increased in cardiac tissue after KF treatment.

The histopathological investigation revealed decreased destruction of myofibrils and lesser TUNEL-positive cells in the cardiac tissue of rats treated with KF Feng et al. investigated the role of KF in CH and the molecular mechanism behind it. Interstitial fibrosis, oxidative stress, and apoptosis were also reduced after KF administration P38 and JNK are subfamilies of MAPKs and regulate cell apoptosis Table 1.

Recent studies have reported that LUT exerts cardioprotective effects against myocardial ischemia, coronary artery disease, and HF , Hu et al.

PLB is a SERCA2a inhibitor whose phosphorylation suppresses activity This study verified the enhancing role of LUT on cardiac contractibility in HF Table 1. Epigallocatechin gallate EGCG is a natural polyphenol flavonoid abundant in green tea and is known for its antioxidant properties.

Several studies have shown that EGCG is vital in decreasing oxidative stress in the cardiovascular system For instance, a study by Sheng et al. showed that EGCG attenuates PO-induced CH by suppressing apoptosis and oxidative stress in rats The findings implied the role of EGCG in reducing oxidative stress and apoptosis; EGCG increased the expression of Bcl-2 and telomere repeat-binding factor 2 TRF2 , which are anti-apoptotic agents.

In addition, EGCG reduces oxidative stress in the heart by decreasing the level of MDA and increasing SOD activity According to the cardioprotective effects of EGCG, Muhammad et al. In this regard, Gao et al. investigated the effect of apigenin treatment on improving hypertension and hypertension-induced CH in Wistar-Kyoto rats.

Previous studies have reported that hypoxia-inducible factor HIF -1α mediates CH through its effect on HIMF hypoxia-induced mitogenic factor 38 , Apigenin can exert inhibitory effects on HIF-1α; therefore, Zhu et al. investigated the anti-hypertrophic effects of apigenin by inhibiting HIF-1α.

The result showed that apigenin decreased blood pressure, heart weight, and serum angiotensin II, indicating a positive role of apigenin in hypertension and CH.

Levels of serum and myocardial-free fatty acids also decreased after apigenin treatment. HIF-1α deregulates cardiac metabolism by inhibiting the expression of mitochondrial proteins involved in metabolisms, such as PPARα, CPT-1, and PDK Apigenin improved abnormal myocardial glucolipid metabolism by upregulating PPARα, CPT-1, and PDK-4 via suppressing HIF-1α.

This study revealed that apigenin's anti-hypertrophic effects are associated with its effect on HIF-1α Table 1. Caffeic acid CA is a natural flavonoid found in various foods and herbs, such as coffee, red wine, thyme, sage, and spearmint CA has a wide range of beneficial effects on cellular processes, such as modulating cell growth, proliferation, and anti-inflammatory effects; hence, this molecule could positively affect the cardiovascular system.

It is reported that intravenous administration of caffeic acid decreases blood pressure and improves cardiac function It also exerts cardioprotective effects by reducing MI-related oxidative stress According to the association of CA with the MAPK pathway and the role of this pathway in CH, Ren et al.

indicated inhibitory effects of CA on PO-induced CH. In addition, the treatment improved cardiac function and decreased cardiac fibrosis. The anti-inflammatory and antioxidant effects of delphinidin were well described ROS is a significant mediator of oxidative stress and has a vital role in the development of CH by regulating various signaling pathways and protein kinases NADPH oxidase NOX is an oxidoreductase enzyme and the leading producer of ROS in cardiac myocytes , Previous studies have shown that delphinidin exerts parts of its function by regulating NOX activity.

Chen et al. showed that treatment with a high dosage of delphinidin ameliorated CH and cardiac dysfunction and reduced oxidative stress and cardiac fibrosis in the heart.

Treatment with delphinidin prevented the increased expression of NOX by activating AMPK, a NOX inhibitor, in response to hypertrophic stimulators. Hesperidin 3,5,7-trihydroxyflavanone 7-rhamnoglucoside HES is a natural flavonoid with comprehensive pharmacological properties such as anti-inflammatory and antioxidant HES has beneficial cardioprotective effects, especially in attenuating CH It was indicated that treatment with HES improved hemodynamic state and attenuated left ventricular function.

HES preserved the function and structure of mitochondria, myofibril, and myocyte. Cardiac injury, apoptosis, and inflammatory markers were decreased, and oxidative stress was reduced in heart tissue by HES treatment.

PPAR-γ is a metabolism regulator which suppresses CH. Bhargava et al. showed that HES upregulated the expression of PPAR-γ, indicating that HES anti-hypertrophic effects arise from enhancing PPAR-γ expression Table 1.

Bioavailability is an essential issue regarding the clinical application of pharmacological substances. The concentration of RES is dose-depended, and the maximal concentration of 2.

Drug delivery systems and reformed formulation are novel ways to improve the bioavailability of RES in humans. RES has been shown to improve myocardial reperfusion, enhancing re-endothelialization and reducing inflammation.

Also, RES consumption before MI reduced infarct size and cardiac arrhythmia and relieved myocardial injury faster. RES can increase the viability and proliferation of cardiac stem cells, therefor transplanting RES-treated stem cells into an ischemic heart improved cardiac injury in the peri-infarct zone While curcumin could be administered as a drug, pure curcumin has low oral bioavailability due to its low absorption and rapid metabolism.

In this regard, Ray et al. Collectively, Ray et al. showed that an efficiently targeted delivery regimen for curcumin enhances its therapeutic effects, reduces CH, and improves cardiac function Additionally, Sungawa et al.

investigated the effectiveness of a novel surfactant-soluble oral drug delivery system DDS for curcumin to develop a therapeutic aid for patients with MI-induced HF.

This DDS significantly enhanced gastrointestinal absorption and effectiveness of curcumin, as administration of 0. In the meantime, no significant side effects were detected regarding DDS curcumin administration.

The histopathologic examination showed that DDS curcumin suppressed myocardial cell hypertrophy and perivascular fibrosis. However, the exact dosage of pure oral curcumin did not apply the same effects Creating a synthetic analog for curcumin is another way to increase its bioavailability to use it as an efficient therapeutic drug.

Shimizu et al. examined the role of five different curcumin analogs in inhibiting pHAT. Among these five analogues, GO-Y 1E, 4E -1,5-bis[3,5-bis methoxymethoxy phenyl]-1,4-pentadieneone inhibited pHAT and improved HF more efficiently than curcumin. The in-vivo investigation conducted by Shimizu et al.

revealed that administration of 0. HF treatment is based on improving symptoms and preventing further complications. Although these treatments effectively relieve symptoms, the survival rate has not met the desirable goal yet.

Therefore, recent studies and clinical trials have focused on targeting the pathogenic mechanism of HF such as myocardial contractibility and metabolism, inflammation, oxidative stress, etc.

with new drugs , Therefore, Gal et al. investigated the role of RES on left ventricular function and cardiac inflammation in patients with HF. Moreover, the levels of NT-proBNP a marker of the severity of HF and galectin-3 were significantly lower in the RES-treated group compared to the placebo group.

Echocardiography results showed that treatment with RES significantly increased ejection fraction, left ventricular stroke volume, left ventricular end-systolic volume, and ventricular dilation, indicating positive effects of RES on cardiac remodeling.

The results showed that RES suppressed the expression of ATP synthesis-related genes via oxidative phosphorylation in leukocytes; however, this did not result in mitochondrial dysfunction. This clinical study demonstrated that RES has anti-inflammatory effects and improves the quality of life, physical performance, cardiac function, and remodeling in patients with MI-induced HF In another similar study, Gal et al.

evaluated the effects of RES on hemorheological parameters in HF patients. They found that RES could significantly improve impaired red blood cell RBC aggregation resulting from HF, which may be attributed to the antioxidative effects of RES.

Also, the result showed that RES significantly improved the results of the 6-minute walk test of HF patients Various cardiovascular disorders are associated with increased RBC aggregation, such as ischemic heart disease, diabetes, venous thrombosis, and HF Increased levels of inflammatory cytokines and oxidants in the blood due to HF are significant factors in RBC aggregation and hemorheological disturbances , Unstable angina, a subtype of acute coronary syndrome ACS , leads to cardiac complications, such as arrhythmia, MI, and eventually HF.

Inflammation is a critical factor in the progression of ACS, leading to further complications. According to the anti-inflammatory effects of curcumin, it can be used as a therapeutic drug in ACS, preventing complications such as HF.

Dastani et al. This novel clinical trial showed no significant effect of curcumin on preventing cardiovascular complications of unstable angina, such as HF The results indicated that high curcumin absorption had no significant effects on left ventricular diastolic function but significantly suppressed increment in the plasma BNP levels The result revealed that nano-curcumin reduced atherosclerosis and hs-CRP levels as an inflammation indicator in diabetic heart patients However, future studies still need to investigate the theory more widely.

As reviewed earlier, polyphenols can play a critical role in attenuating HF and CH, as they can prevent cardiac remodeling mechanistically by blocking oxidative, inflammatory, apoptotic, and fibrotic-related pathways.

Moreover, polyphenols are easily accessible and enriched within various natural plant-based sources and could be considered novel promising therapeutic approaches for HF. Additionally, the conventional HF treatments' low survival rates have forced studies to search for other viable options as CVDs are growing globally.

However, these studies are still in their infancy, and limited clinical data regarding the efficacy, side effects, and administration routes of polyphenol-based drugs for treating cardiovascular diseases such as HF and CH are available.

Despite the abundant presence of polyphenols in a human's regular nutritional diet, the poor solubility, low stability, rapid metabolism and elimination, and eventually, weak bioavailability are the rate-limiting factors for inhibiting these compounds from exerting their full cardioprotective effects Therefore, some recent studies have focused on enhancing the polyphenols' bioavailability, especially RES and curcumin, by employing nanoformulations, such as lipid-based nanoparticles liposomes , protein-based nanoformulations, polymers, micelles, and metal nanoparticles for drug delivery For instance, RES and curcumin co-delivery by polymeric micelles to doxorubicin-treated cardiomyocyte cell lines resulted in higher drug solubility and efficacy than non-polymeric forms and single-drug treatment Polymeric micelles used in these studies are biocompatible and FDA-approved.

Moreover, polymer-based drug delivery vehicles such as Poly D,L-lactic-co-glycolic acid PLGA nanoparticles demonstrated superior anti-atherosclerotic effects of curcumin-bioperine treatment compared to non-coated ones.

Pillai et al. reported that curcumin-bioperine coated with PLGA nanoparticles significantly reduced ox-LDL levels, downregulating the atherosclerotic plaque-related gene expression in vitro The efficacy of PLGA-encapsulated curcumin was also illustrated in vivo in later studies, where gold-capped curcumin encapsulated within PLGA demonstrated enhanced solubility, bioavailability, and eventually, improved anti-hypertrophic characteristics in hypertrophic Wistar rat models Aside from polymeric-based drug delivery, extensive studies were carried out on the efficacy of liposome-targeted therapy — Liposomes are phospholipid-based nanocarriers designed for both hydrophilic and hydrophobic drug delivery.

Liposome preparation progress in recent years has introduced the ligand surface-engineered and long-circulating liposomes, allowing stability and sustained drug release in target tissues and enhanced bioavailability The use of liposomes in CVDs has become a promising candidate for future safe drug delivery without cytotoxicity.

RES-contained liposomes were demonstrated to enhance the respiratory capacity of the cardiomyocytes in vitro Moreover, the transplantation of mitochondrial-activated cardiac progenitor cells by liposomal RES into the heart of the mouse models with cardiomyopathy resulted in reduced oxidative stress and apoptotic activities of the cardiomyocytes Considering their minimal side effects and significant therapeutic features, polyphenols have introduced themselves as intriguing options for future HF treatment.

However, due to the low bioavailability and stability of polyphenols in the circulating system, limited clinical trials have been conducted evaluating their impact on human HF, and most of the studies are in vitro and in vivo animal models.

However, with recent advances in novel drug delivery systems, there is rising hope for translating nanoparticle delivery of these compounds to the clinical setting soon. In conclusion, this study predominantly reviewed the therapeutic effects of polyphenol compounds and their underlying mechanisms in improving pathologic cardiac remodeling, leading to heart failure.

Also, this study discusses the most recent advances and challenges in translating the antioxidative, anti-inflammatory, anti-apoptotic, and antifibrotic characteristics of these nutraceuticals into clinical settings.

The potential application of nano-drug delivery systems was also investigated regarding the limited solubility, stability, and bioavailability of the polyphenols in humans. Finally, further in-depth surveys are needed to understand better the involved molecular pathways of polyphenols in modulating cardiac remodeling and HF.

Also, there is a rising demand for viable strategies to better translate the in vitro and animal study results into the clinic. NH, AY, MS, YG, FA, RE, M-HA, MH, ZA, HM, MHJ, AM, and MR took part in creating the idea, design, and composing of the manuscript.

All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Ooi BK, Chan K-G, Goh BH, Yap WH. The role of natural products in targeting cardiovascular diseases via Nrf2 pathway: novel molecular mechanisms and therapeutic approaches. Front Pharmacol. doi: PubMed Abstract CrossRef Full Text Google Scholar.

Rana A, Samtiya M, Dhewa T, Mishra V, Aluko RE. Health benefits of polyphenols: a concise review. J Food Biochem. Tangney CC, Rasmussen HE.

Polyphenols, inflammation, and cardiovascular disease. Curr Atheroscler Rep. CrossRef Full Text Google Scholar. de Paulo Farias D, Neri-Numa IA, de Araujo FF, Pastore GM. A critical review of some fruit trees from the Myrtaceae family as promising sources for food applications with functional claims.

Food Chem. Zhang Z, Qiu C, Li X, McClements DJ, Jiao A, Wang J, et al. Advances in research on interactions between polyphenols and biology-based nano-delivery systems and their applications in improving the bioavailability of polyphenols. Trends Food Sci Technol. Chen G-L, Fan M-X, Wu J-L, Li N, Guo M-Q.

Antioxidant and anti-inflammatory properties of flavonoids from lotus plumule. Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longevity.

Sarker U, Oba S. Polyphenol and flavonoid profiles and radical scavenging activity in leafy vegetable Amaranthus gangeticus. BMC Plant Biol. Bharti R, Khamparia A, Shabaz M, Dhiman G, Pande S, Singh P. Prediction of heart disease using a combination of machine learning and deep learning. Comput Intell Neurosci.

Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol. Bragazzi NL, Zhong W, Shu J, Abu Much A, Lotan D, Grupper A, et al.

Burden of heart failure and underlying causes in countries and territories from to Eur J Prev Cardiol. Gallo S, Vitacolonna A, Bonzano A, Comoglio P, Crepaldi T. ERK: a key player in the pathophysiology of cardiac hypertrophy.

Int J Mol Sci. McCarty MF. Nutraceutical, dietary, and lifestyle options for prevention and treatment of ventricular hypertrophy and heart failure. Chang X, Zhang T, Zhang W, Zhao Z, Sun J. Natural drugs as a treatment strategy for cardiovascular disease through the regulation of oxidative stress.

Google Scholar. Mollace V, Rosano GM, Anker SD, Coats AJ, Seferovic P, Mollace R, et al. Pathophysiological basis for nutraceutical supplementation in heart failure: a comprehensive review.

Kutan Fenercioglu A, Saler T, Genc E, Sabuncu H, Altuntas Y. The effects of polyphenol-containing antioxidants on oxidative stress and lipid peroxidation in type 2 diabetes mellitus without complications.

J Endocrinol Investig. Cheng Y-C, Sheen J-M, Hu WL, Hung Y-C. Polyphenols and oxidative stress in atherosclerosis-related ischemic heart disease and stroke. Brito PM, Devillard R, Nègre-Salvayre A, Almeida LM, Dinis TC, Salvayre R, et al. Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells.

Sung MM, Das SK, Levasseur J, Byrne NJ, Fung D, Kim TT, et al. Resveratrol treatment of mice with pressure-overloadinduced heart failure improves diastolic function and cardiac energy metabolism.

Circ Heart Fail. Ahmet I, Tae H-J, Lakatta EG, Talan M. Long-term low dose dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in chronic heart failure in rats.

Can J Physiol Pharmacol. Rimbaud S, Ruiz M, Piquereau J, Mateo P, Fortin D, Veksler V, et al. Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure. PLoS One.

Matsumura N, Takahara S, Maayah ZH, Parajuli N, Byrne NJ, Shoieb SM, et al. Resveratrol improves cardiac function and exercise performance in MI-induced heart failure through the inhibition of cardiotoxic HETE metabolites.

J Mol Cell Cardiol. Bahit MC, Kochar A, Granger CB. Post-myocardial infarction heart failure. JACC Heart Fail. Martin AC, Bories MC, Tence N, Baudinaud P, Pechmajou L, Puscas T, et al.

Epidemiology, pathophysiology, and management of native atrioventricular valve regurgitation in heart failure patients. Front Cardiovasc Med. Slivnick J, Lampert BC. Hypertension and heart failure. Heart Fail Clin. Rosenbaum AN, Agre KE, Pereira NL.

Genetics of dilated cardiomyopathy: practical implications for heart failure management. Nat Rev Cardiol. Lehrke M, Marx N. Diabetes mellitus and heart failure. Am J Cardiol. Bracamonte-Baran W, Čiháková D. Cardiac autoimmunity: myocarditis. Adv Exp Med Biol.

Lyon RC, Zanella F, Omens JH, Sheikh F. Mechanotransduction in cardiac hypertrophy and failure. Circ Res. Dhalla NS, Saini-Chohan HK, Rodriguez-Leyva D, Elimban V, Dent MR, Tappia PS. Subcellular remodelling may induce cardiac dysfunction in congestive heart failure. Cardiovasc Res.

Lin YT, Lin YH, Wu XM, Ko CL, Yen RF, Chen YH, et al. The relationship between serum fibrosis markers and restrictive ventricular filling in patients with heart failure with reduced ejection fraction: a technetiumm radionuclide ventriculography study. Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction.

Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. He J, Luo Y, Song J, Tan T, Zhu H. Non-coding RNAs and pathological cardiac hypertrophy. Shah AK, Bhullar SK, Elimban V, Dhalla NS.

Oxidative stress as a mechanism for functional alterations in cardiac hypertrophy and heart failure. Antioxidants Basel. Shimizu I, Minamino T.

Physiological and pathological cardiac hypertrophy. van Berlo JH, Maillet M, Molkentin JD. Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest. Kumar S, Wang G, Liu W, Ding W, Dong M, Zheng N, et al.

Hypoxia-induced mitogenic factor promotes cardiac hypertrophy via calcium-dependent and hypoxia-inducible factor-1α mechanisms. Senoner T, Dichtl W. Oxidative stress in cardiovascular diseases: still a therapeutic target? Strassheim D, Dempsey EC, Gerasimovskaya E, Stenmark K, Karoor V.

Role of inflammatory cell subtypes in heart failure. J Immunol Res. Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role of inflammation in heart failure. Hall C, Gehmlich K, Denning C, Pavlovic D. Complex relationship between cardiac fibroblasts and cardiomyocytes in health and disease.

J Am Heart Assoc. Kanagala P, Cheng ASH, Singh A, Khan JN, Gulsin GS, Patel P, et al. Relationship between focal and diffuse fibrosis assessed by CMR and clinical outcomes in heart failure with preserved ejection fraction. JACC Cardiovasc Imaging. Milinković I, Polovina M, Simeunović DS, Ašanin M, Seferović PM.

Oxidative stress and inflammation in heart failure: the best is yet to come. Wu S, Lan J, Li L, Wang X, Tong M, Fu L, et al. Cell Biol Toxicol. Juhasz B, Varga B, Gesztelyi R, Kemeny-Beke A, Zsuga J, Tosaki A. Resveratrol: a multifunctional cytoprotective molecule.

Curr Pharm Biotechnol. Vuolo MM, Lima VS, Junior MRM. Phenolic compounds: structure, classification, and antioxidant power. In: Bioactive compounds. Amesterdam, Netherlands: Elsevier Gómez-Caravaca AM, Verardo V, Segura-Carretero A, Fernández-Gutiérrez A, Caboni MF. Phenolic compounds and saponins in plants grown under different irrigation regimes.

In: Polyphenols in plants. Behl T, Bungau S, Kumar K, Zengin G, Khan F, Kumar A, et al. Pleotropic effects of polyphenols in cardiovascular system. Biomed Pharmacother. Zeb A, Zeb A. Concept of antioxidants in foods. In: Phenolic antioxidants in foods: Chemistry, biochemistry and analysis Amesterdam, Netherlands: Springer Rasul A, Millimouno FM, Ali Eltayb W, Ali M, Li J, Li X.

Pinocembrin: a novel natural compound with versatile pharmacological and biological activities. BioMed Res Int.

Mihanfar A, Nouri M, Roshangar L, Khadem-Ansari MH. Polyphenols: natural compounds with promising potential in treating polycystic ovary syndrome. Reprod Biol. Salami M, Salami R, Mafi A, Aarabi MH, Vakili O, Asemi Z. Therapeutic potential of resveratrol in diabetic nephropathy according to molecular signaling.

Current Molecular Pharmacology. Ahmadi A, Mazloomnejad R, Kasravi M, Gholamine B, Bahrami S, Sarzaeem MM, et al. Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways. Pathak S, Kesavan P, Banerjee A, Banerjee A, Celep GS, Bissi L, et al.

Metabolism of dietary polyphenols by human gut microbiota and their health benefits. In: Polyphenols: Mechanisms of action in human health and disease. Elsevier de Araْjo FF, de Paulo Farias D, Neri-Numa IA, Pastore GM. Polyphenols and their applications: an approach in food chemistry and innovation potential.

Cui Q, Du R, Liu M, Rong L. Lignans and their derivatives from plants as antivirals. Rodríguez-García C, Sánchez-Quesada C, Toledo E, Delgado-Rodríguez M, Gaforio JJ. Naturally lignan-rich foods: a dietary tool for health promotion? Calado A, Neves PM, Santos T, Ravasco P. The effect of flaxseed in breast cancer: a literature review.

Front Nutr. Liu W, Lu Y, Chu S, Jiang M, Bai G. J Funct Foods. Hu Y, Li Y, Sampson L, Wang M, Manson JE, Rimm E, et al. Lignan intake and risk of coronary heart disease. J Am Coll Cardiol. Akrami A, Nikaein F, Babajafari S, Faghih S, Yarmohammadi H.

Comparison of the effects of flaxseed oil and sunflower seed oil consumption on serum glucose, lipid profile, blood pressure, and lipid peroxidation in patients with metabolic syndrome. J Clin Lipidol. Hasaniani N, Rahimlou M, Ahmadi AR, Khalifani AM, Alizadeh M.

The effect of flaxseed enriched yogurt on the glycemic status and cardiovascular risk factors in patients with type 2 diabetes mellitus: randomized, open-labeled, controlled study. Clin Nutr Res. Câmara JS, Albuquerque BR, Aguiar J, Corrêa RC, Gonçalves JL, Granato D, et al.

Food bioactive compounds and emerging techniques for their extraction: polyphenols as a case study. Zhang L-X, Li C-X, Kakar MU, Khan MS, Wu P-F, Amir RM, et al. Resveratrol RV : a pharmacological review and call for further research. Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, et al.

Resveratrol: a double-edged sword in health benefits. Nabeebaccus A, Zhang M, Shah AM. NADPH oxidases and cardiac remodelling. Heart Fail Rev. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease.

Exp Mol Med. Sivandzade F, Prasad S, Bhalerao A, Cucullo L. NRF2 and NF-κB interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol. Wardyn JD, Ponsford AH, Sanderson CM. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways.

Biochem Soc Trans. Saha S, Buttari B, Panieri E, Profumo E, Saso L. An overview of Nrf2 signaling pathway and its role in inflammation.

Buelna-Chontal M, Zazueta C. Cell Signal. Chauhan A, Islam AU, Prakash H, Singh S. Phytochemicals targeting NF-κB signaling: potential anti-cancer interventions. J Pharm Anal. Khan H, Ullah H, Castilho PCMF, Gomila AS, D'Onofrio G, Filosa R, et al.

Targeting NF-κB signaling pathway in cancer by dietary polyphenols. Crit Rev Food Sci Nutr. Chen M, Chen Z, Huang D, Sun C, Xie J, Chen T, et al. Pulm Pharmacol Ther. Marino A, Hausenloy DJ, Andreadou I, Horman S, Bertrand L, Beauloye C. AMP-activated protein kinase: a remarkable contributor to preserve a healthy heart against ROS injury.

Free Radic Biol Med. Najjar RS, Feresin RG. Protective role of polyphenols in heart failure: molecular targets and cellular mechanisms underlying their therapeutic potential.

Jin L, Piao ZH, Sun S, Liu B, Kim GR, Seok YM, et al. Gallic acid reduces blood pressure and attenuates oxidative stress and cardiac hypertrophy in spontaneously hypertensive rats. Sci Rep. Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GW, Kitsis RN, et al.

Mitochondrial function, biology, and role in disease: a scientific statement from the American heart association. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. Skemiene K, Rakauskaite G, Trumbeckaite S, Liobikas J, Brown GC, Borutaite V.

Anthocyanins block ischemia-induced apoptosis in the perfused heart and support mitochondrial respiration potentially by reducing cytosolic cytochrome c. Int J Biochem Cell Biol. Rodríguez-García C, Sánchez-Quesada C, Toledo E, Delgado-Rodríguez M, Gaforio JJ Naturally lignan-rich foods: a dietary tool for health promotion?

Mutha RE, Tatiya AU, Surana SJ Flavonoids as natural phenolic compounds and their role in therapeutics: an overview. Future J Pharm Sci 7. Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: an overview.

Medicines 5. Zhao J, Yang J, Xie Y Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: an overview. Int J Pharm Kumar S, Pandey AK Chemistry and biological activities of flavonoids: an overview.

Sci World J Panche AN, Diwan AD, Chandra SR Flavonoids: an overview. J Nutr Sci 5:e Amarowicz R, Pegg RB The potential protective effects of phenolic compounds against low-density lipoprotein oxidation. Bouarab Chibane L, Degraeve P, Ferhout H, Bouajila J, Oulahal N Plant antimicrobial polyphenols as potential natural food preservatives.

J Sci Food Agric — Leyva-Jimenez FJ, Lozano-Sanchez J, Borras-Linares I, de la Cadiz-Gurrea ML, Mahmoodi-Khaledi E Potential antimicrobial activity of honey phenolic compounds against gram positive and gram negative bacteria.

LWT Aguirre-Becerra H, Pineda-Nieto SA, García-Trejo JF, Guevara-González RG, Feregrino-Pérez AA, Álvarez-Mayorga BL, Rivera Pastrana DM Jacaranda flower Jacaranda mimosifolia as an alternative for antioxidant and antimicrobial use. Heliyon 6. Takó M, Kerekes EB, Zambrano C, Kotogán A, Papp T, Krisch J, Vágvölgyi C Plant phenolics and phenolic-enriched extracts as antimicrobial agents against food-contaminating microorganisms.

Antioxidants Mammadov R, Kaska A, Ozay C Phenolic composition, antioxidant and cytotoxic activities of Prospero autumnale. Indian J Pharm Sci Yang CS, Landau JM, Huang MT, Newmark HL Inhibition of carcinogenesis by dietary polyphenolic compounds.

Annu Rev Nutr — Friedman MC Biochemistry, and dietary role of potato polyphenols. A review. J Agric Food Chem — Olivas-Quintero S, López-Angulo G, Montes-Avila J, Díaz-Camacho SP, Vega-Aviña R, López-Valenzuela JÁ, Salazar-Salas NY, Delgado-Vargas F Chemical composition and biological activities of Helicteres vegae and Heliopsis sinaloensis.

Pharm Biol Chariyakornkul A, Punvittayagul C, Taya S, Wongpoomchai R Inhibitory effect of purple rice husk extract on AFB1-induced micronucleus formation in rat liver through modulation of xenobiotic metabolizing enzymes.

BMC Complement Altern Med Mushtaq M, Sultana B, Anwar F, Batool S Antimutagenic and antioxidant potential of aqueous and acidified methanol extracts from citrus limonum fruit residues. J Chil Chem Soc Beaver C, Collins TS, Harbertson J Red wine phenolic compounds using ultraviolet — visible spectra.

Molecules —8. Fourie E, Aleixandre-Tudo JL, Mihnea M, du Toit W Partial least squares calibrations and batch statistical process control to monitor phenolic extraction in red wine fermentations under different maceration conditions. Food Control Fang X, Azain M, Crowe-White K, Mumaw J, Grimes JA, Schmiedt C, Barletta M, Rayalam S, Park HJ Effect of acute ingestion of green tea extract and lemon juice on oxidative stress and lipid profile in pigs fed a high-fat diet.

Antioxidants 8. Ahn-Jarvis JH, Parihar A, Doseff AI Dietary flavonoids for immunoregulation and cancer: food design for targeting disease.

Buttar HS, Li T, Ravi N Prevention of cardiovascular diseases: role of exercise, dietary interventions, obesity and smoking cessation. Exp Clin Cardiol — Katz DL, Doughty K, Ali A Cocoa and chocolate in human health and disease.

Antioxid Redox Signal — Huxley RR, Neil HAW The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies.

Eur J Clin Nutr — Lagiou P, Samoli E, Lagiou A, Tzonou A, Kalandidi A, Peterson J, Dwyer J, Trichpoulos D Intake of specific flavonoid classes and coronary heart disease — a case-control study in Greece. Eur J Clin Nutr Rimm EB, Katan MB, Ascherio A, Stampfer MJ, Willett WC Relation between intake of flavonoids and risk for coronary heart disease in male health professionals.

Ann Intern Med Hirvonen T, Pietinen P, Virtanen M, Ovaskainen ML, Häkkinen S, Albanes D, Virtamo J Intake of flavonols and flavones and risk of coronary heart disease in male smokers. Epidemiology Bondonno NP, Dalgaard F, Kyrø C, Murray K, Bondonno CP, Lewis JR, Croft KD, Gislason G, Scalbert A, Cassidy A et al Flavonoid intake is associated with lower mortality in the Danish diet cancer and health cohort.

Nat Commun Peterson JJ, Dwyer JT, Jacques PF, McCullough ML Do flavonoids reduce cardiovascular disease incidence or mortality in US and European populations?

Nutr Rev — PubMed Google Scholar. Kruger MJ, Davies N, Myburgh KH, Lecour S Proanthocyanidins, anthocyanins and cardiovascular diseases.

Food Res Int — CAS Google Scholar. Wallace TC Anthocyanins in cardiovascular disease. Adv Nutr —7. Gardner EJ, Ruxton CHS, Leeds AR Black tea — helpful or harmful? A review of the evidence. Article CAS PubMed Google Scholar.

Li D, Wang R, Huang J, Cai Q, Yang CS, Wan X, Xie Z Effects and mechanisms of tea regulating blood pressure: evidences and promises.

Nutrients E Igho-Osagie E, Cara K, Wang D, Yao Q, Penkert LP, Cassidy A, Ferruzzi M, Jacques PF, Johnson EJ, Chung M et al Short-term tea consumption is not associated with a reduction in blood lipids or pressure: a systematic review and meta-analysis of randomized controlled trials.

J Nutr Tuteja N, Chandra M, Tuteja R, Misra MK Nitric oxide as a unique bioactive signaling messenger in physiology and pathophysiology. J Biomed Biotechnol — Förstermann U, Sessa WC Nitric oxide synthases: regulation and function.

Eur Heart J — Blumberg JB, Vita JA, Oliver Chen CY Concord grape juice polyphenols and cardiovascular risk factors: dose-response relationships.

Nutrients 7. Duffy SJ, Vita JA, Holbrook M, Swerdloff PL, Keaney JF Effect of acute and chronic tea consumption on platelet aggregation in patients with coronary artery disease. Arterioscler Thromb Vasc Biol McEwen BJ The influence of diet and nutrients on platelet function.

Semin Thromb Hemost Rees A, Dodd GF, Spencer JPE The effects of flavonoids on cardiovascular health: a review of human intervention trials and implications for cerebrovascular function. Peters U, Poole C, Arab L Does tea affect cardiovascular disease? A meta-analysis.

Am J Epidemiol Tresserra-Rimbau A, Rimm EB, Medina-Remón A, Martínez-González MA, López-Sabater MC, Covas MI, Corella D, Salas-Salvadó J, Gómez-Gracia E, Lapetra J et al Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial. BMC Med Tresserra-Rimbau A, Medina-Remón A, Pérez-Jiménez J, Martínez-González MA, Covas MI, Corella D, Salas-Salvadó J, Gómez-Gracia E, Lapetra J, Arós F et al Dietary intake and major food sources of polyphenols in a Spanish population at high cardiovascular risk: the PREDIMED study.

Sarwar N, Gao P, Kondapally Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M et al Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of prospective studies.

Lancet London, England — Anand SS, Dagenais GR, Mohan V, Diaz R, Probstfield J, Freeman R, Shaw J, Lanas F, Avezum A, Budaj A et al Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study.

Eur J Prev Cardiol Low Wang CC, Hess CN, Hiatt WR, Goldfine AB Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus — mechanisms, management, and clinical considerations.

Circulation Paulus WJ, Dal Canto E Distinct myocardial targets for diabetes therapy in heart failure with preserved or reduced ejection fraction. JACC Heart Fail —7. Jia G, Hill MA, Sowers JR Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res — Castagno D, Baird-Gunning J, Jhund PS, Biondi-Zoccai G, MacDonald MR, Petrie MC, Gaita F, McMurray JJV Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37, patient meta-analysis.

Am Heart J Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson A-M, Zethelius B, Miftaraj M, McGuire DK, Rosengren A et al Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.

N Engl J Med Ernande L, Audureau E, Jellis CL, Bergerot C, Henegar C, Sawaki D, Czibik G, Volpi C, Canoui-Poitrine F, Thibault H et al Clinical implications of echocardiographic phenotypes of patients with diabetes mellitus.

J Am Coll Cardiol Gach O, El Husseini Z, Lancellotti P Acute coronary syndrome. Rev Med Liege Lancet Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes the MIRACL study: a randomized controlled trial.

J Am Med Assoc Mikhail N Effects of Evolocumab on cardiovascular events. Curr Cardiol Rev Zieske AW, Takei H, Fallon KB, Strong JP Smoking and atherosclerosis in youth.

Atherosclerosis Hardman RL, Jazaeri O, Yi J, Smith M, Gupta R Overview of classification systems in peripheral artery disease. Semin Intervent Radiol — Soran H, Dent R, Durrington P Evidence-based goals in LDL-C reduction.

Clin Res Cardiol — Aune D, Schlesinger S, Norat T, Riboli E Tobacco smoking and the risk of abdominal aortic aneurysm: a systematic review and meta-analysis of prospective studies. Sci Rep 8. Jha P The hazards of smoking and the benefits of cessation: a critical summation of the epidemiological evidence in high-income countries.

elife 9. Warner TD, Nylander S, Whatling C Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br J Clin Pharmacol — Mattiello T, Trifirò E, Jotti GS, Pulcinelli FM Effects of pomegranate juice and extract polyphenols on platelet function.

J Med Food Karlíčková J, Říha M, Filipský T, Macáková K, Hrdina R, Mladěnka P Antiplatelet effects of flavonoids mediated by inhibition of arachidonic acid based pathway. Planta Med Wu CM, Wu SC, Chung WJ, Lin HC, Chen KT, Chen YC, Hsu MF, Yang JM, Wang JP, Lin CN Antiplatelet effect and selective binding to cyclooxygenase COX by molecular docking analysis of flavonoids and lignans.

Int J Mol Sci 8. Calixto NO, E Silva MCDC, Gayer CRM, Coelho MGP, Paes MC, Todeschini AR Antiplatelet activity of geranylgeraniol isolated from Pterodon pubescens fruit oil is mediated by inhibition of cyclooxygenase Nurtjahja-Tjendraputra E, Ammit AJ, Roufogalis BD, Tran VH, Duke CC Effective anti-platelet and COX-1 enzyme inhibitors from pungent constituents of ginger.

Thromb Res Bijak M, Saluk-Bijak J Flavonolignans inhibit the arachidonic acid pathway in blood platelets. Toxicol Appl Pharmacol — Applová L, Karlíčková J, Říha M, Filipský T, Macáková K, Spilková J, Mladěnka P The isoflavonoid tectorigenin has better antiplatelet potential than acetylsalicylic acid.

Phytomedicine Guerrero JA, Lozano ML, Castillo J, Benavente-García O, Vicente V, Rivera J Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor.

J Thromb Haemost 3. Lee JJ, Jin YR, Lim Y, Hong JT, Kim TJ, Chung JH, Yun YP Antiplatelet activity of carnosol is mediated by the inhibition of TXA2 receptor and cytosolic calcium mobilization. Vasc Pharmacol Srivastava KC, Tyagi OD Effects of a garlic-derived principle ajoene on aggregation and arachidonic acid metabolism in human blood platelets.

Prostaglandins Leukot Essent Fat Acids Ju HK, Lee JG, Park MK, Park SJ, Lee CH, Park JH, Kwon SW Metabolomic investigation of the anti-platelet aggregation activity of ginsenoside Rk1 reveals attenuated HETE production. J Proteome Res Hanssen NMJ, Wouters K, Huijberts MS, Gijbels MJ, Sluimer JC, Scheijen JLJM, Heeneman S, Biessen EAL, Daemen MJAP, Brownlee M et al Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype.

Eur Heart J Rabbani N, Thornalley PJ Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int — Lo CY, Hsiao WT, Chen XY Efficiency of trapping methylglyoxal by phenols and phenolic acids.

J Food Sci Totlani VM, Peterson DG Epicatechin carbonyl-trapping reactions in aqueous Maillard systems: identification and structural elucidation. J Agric Food Chem Vlassara H, Cai W, Tripp E, Pyzik R, Yee K, Goldberg L, Tansman L, Chen X, Mani V, Fayad ZA et al Oral AGE restriction ameliorates insulin resistance in obese individuals with the metabolic syndrome: a randomised controlled trial.

Diabetologia Baye E, Kiriakova V, Uribarri J, Moran LJ, De Courten B Consumption of diets with low advanced glycation end products improves cardiometabolic parameters: meta-analysis of randomised controlled trials.

Sci Rep 7. Rodríguez JM, Leiva Balich L, Concha MJ, Mizón C, Bunout Barnett D, Barrera Acevedo G, Hirsch Birn S, Jiménez Jaime T, Henríquez S, Uribarri J et al Reduction of serum advanced glycation end-products with a low calorie Mediterranean diet.

Nutr Hosp Lopez-Moreno J, Quintana-Navarro GM, Delgado-Lista J, Garcia-Rios A, Alcala-Diaz JF, Gomez-Delgado F, Camargo A, Perez-Martinez P, Tinahones FJ, Striker GE et al Mediterranean diet supplemented with coenzyme Q 10 modulates the postprandial metabolism of advanced glycation end products in elderly men and women.

J Gerontol A Biol Sci Med Sci Urquiaga I, Ávila F, Echeverria G, Perez D, Trejo S, Leighton F A Chilean berry concentrate protects against postprandial oxidative stress and increases plasma antioxidant activity in healthy humans.

Oxidative Med Cell Longev Shao B, Pennathur S, Pagani I, Oda MN, Witztum JL, Oram JF, Heinecke JW Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway.

J Biol Chem Pamplona R, Portero-Otín M, Riba D, Requena JR, Thorpe SR, López-Torres M, Barja G Low fatty acid unsaturation: a mechanism for lowered lipoperoxidative modification of tissue proteins in mammalian species with long life spans.

Ruiz MC, Ayala V, Portero-Otín M, Requena JR, Barja G, Pamplona R Protein methionine content and MDA-lysine adducts are inversely related to maximum life span in the heart of mammals. Mech Ageing Dev Ramkissoon JS, Mahomoodally MF, Ahmed N, Subratty AH Antioxidant and anti-glycation activities correlates with phenolic composition of tropical medicinal herbs.

Asian Pac J Trop Med 6. Harris CS, Cuerrier A, Lamont E, Haddad PS, Arnason JT, Bennett SAL, Johns T Investigating wild berries as a dietary approach to reducing the formation of advanced glycation endproducts: chemical correlates of in vitro antiglycation activity.

Plant Foods Hum Nutr Kokkinidou S, Peterson DG Response surface methodology as optimization strategy for reduction of reactive carbonyl species in foods by means of phenolic chemistry. Food Funct 4. Li X, Zheng T, Sang S, Lv L Quercetin inhibits advanced glycation end product formation by trapping methylglyoxal and glyoxal.

Lv L, Shao XI, Wang L, Huang D, Ho CT, Sang S Stilbene glucoside from polygonum multiflorum thunb. Shen Y, Xu Z, Sheng Z Ability of resveratrol to inhibit advanced glycation end product formation and carbohydrate-hydrolyzing enzyme activity, and to conjugate methylglyoxal.

Food Chem Van Den Eynde MDG, Geleijnse JM, Scheijen JLJM, Hanssen NMJ, Dower JI, Afman LA, Stehouwer CDA, Hollman PCH, Schalkwijk CG Quercetin, but not epicatechin, decreases plasma concentrations of methylglyoxal in adults in a randomized, double-blind, placebo-controlled, crossover trial with pure flavonoids.

Dower JI, Geleijnse JM, Gijsbers L, Zock PL, Kromhout D, Hollman PCH Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized, double-blind, placebo-controlled, crossover trial. Zordoky BNM, Robertson IM, Dyck JRB Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases.

Biochim Biophys Acta Mol basis Dis — Zhang N, Wei WY, Li LL, Hu C, Tang QZ Therapeutic potential of polyphenols in cardiac fibrosis. Front Pharmacol Han X, Gao S, Cheng Y, Sun Y, Liu W, Tang L, Ren D Protective effect of naringeninO-glucoside against oxidative stress induced by doxorubicin in H9c2 cardiomyocytes.

Biosci Trends 6. Repo-Carrasco-Valencia R, Hellström JK, Pihlava JM, Mattila PH Flavonoids and other phenolic compounds in Andean indigenous grains: Quinoa Chenopodium quinoa , kañiwa Chenopodium pallidicaule and kiwicha Amaranthus caudatus. Razavi-Azarkhiavi K, Iranshahy M, Sahebkar A, Shirani K, Karimi G The protective role of phenolic compounds against doxorubicin-induced cardiotoxicity: a comprehensive review.

Nutr Cancer — Sun J, Sun G, Meng X, Wang H, Luo Y, Qin M, Ma B, Wang M, Cai D, Guo P et al Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. PLoS One 8. Korga A, Józefczyk A, Zgórka G, Homa M, Ostrowska M, Burdan F, Dudka J Evaluation of the phytochemical composition and protective activities of methanolic extracts of Centaurea borysthenica and Centaurea daghestanica Lipsky Wagenitz on cardiomyocytes treated with doxorubicin.

Food Nutr Res Alhaider IA, Mohamed ME, Ahmed KKM, Kumar AHS Date palm Phoenix dactylifera fruits as a potential cardioprotective agent: the role of circulating progenitor cells. Article PubMed PubMed Central Google Scholar. Syama HP, Arya AD, Dhanya R, Nisha P, Sundaresan A, Jacob E, Jayamurthy P Quantification of phenolics in Syzygium cumini seed and their modulatory role on tertiary butyl-hydrogen peroxide-induced oxidative stress in H9c2 cell lines and key enzymes in cardioprotection.

J Food Sci Technol Garjani A, Tila D, Hamedeyazdan S, Vaez H, Rameshrad M, Pashaii M, Fathiazad F An investigation on cardioprotective potential of Marrubium vulgare aqueous fraction against ischaemia-reperfusion injury in isolated rat heart.

Folia Morphol Warsz Dludla PV, Joubert E, Muller CJF, Louw J, Johnson R Hyperglycemia-induced oxidative stress and heart disease-cardioprotective effects of rooibos flavonoids and phenylpyruvic acidO-β-D-glucoside.

Nutr Metab Tian J, Wu X, Zhang M, Zhou Z, Liu Y Comparative study on the effects of apple peel polyphenols and apple flesh polyphenols on cardiovascular risk factors in mice.

Clin Exp Hypertens Alcohol Res — Wilsnack RW, Wilsnack SC, Kristjanson AF, Vogeltanz-Holm ND, Gmel G Gender and alcohol consumption: patterns from the multinational GENACIS project. Addiction Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors.

Br Med J Thadhani R, Camargo CA, Stampfer MJ, Curhan GC, Willett WC, Rimm EB Prospective study of moderate alcohol consumption and risk of hypertension in young women. Arch Intern Med Leger ASS, Cochrane AL, Moore F Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine.

Renaud S, de Lorgeril M Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lippi G, Franchini M, Favaloro EJ, Targher G Moderate red wine consumption and cardiovascular disease risk: beyond the French paradox.

Semin Thromb Hemost — Haseeb S, Alexander B, Baranchuk A, Electrophysiology C Wine and cardiovascular health a comprehensive review in depth. Circulation — Ditano-Vázquez P, Torres-Peña JD, Galeano-Valle F, Pérez-Caballero AI, Demelo-Rodríguez P, Lopez-Miranda J, Katsiki N, Delgado-Lista J, Alvarez-Sala-Walther LA The fluid aspect of the mediterranean diet in the prevention and management of cardiovascular disease and diabetes: the role of polyphenol content in moderate consumption of wine and olive oil.

Castaldo L, Narváez A, Izzo L, Graziani G, Gaspari A, Minno G, Di; Ritieni, A. Hansen AS, Marckmann P, Dragsted LO, Finné Nielsen IL, Nielsen SE, Grønbæk M Effect of red wine and red grape extract on blood lipids, haemostatic factors, and other risk factors for cardiovascular disease.

Truelsen T, Grønbæk M, Schnohr P, Boysen G Intake of beer, wine, and spirits and risk of stroke: the Copenhagen City heart study. Stroke Gronbaek M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein HO, Jensen G, Sorensen TIA Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer.

Klatsky AL Moderate drinking and reduced risk of heart disease. Alcohol Res Health — Am J Public Health — Pingitore A, Chambers ES, Hill T, Maldonado IR, Liu B, Bewick G, Morrison DJ, Preston T, Wallis GA, Tedford C et al The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro.

Diabetes Obes Metab Cell Metab Romano KA, Vivas EI, Amador-Noguez D, Rey FE Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide.

MBio 6. Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, Gupta N, Skye SM, Cody DB, Levison BS et al Development of a gut microbe—targeted nonlethal therapeutic to inhibit thrombosis potential.

Nat Med Li Q, Gao B, Siqin B, He Q, Zhang R, Meng X, Zhang N, Zhang N, Li M Gut microbiota: a novel regulator of cardiovascular disease and key factor in the therapeutic effects of flavonoids. Wilson Tang WH, Hazen SL The gut microbiome and its role in cardiovascular diseases.

Pluznick JL Microbial short-chain fatty acids and blood pressure regulation. Curr Hypertens Rep Natarajan N, Hori D, Flavahan S, Steppan J, Flavahan NA, Berkowitz DE, Pluznick JL Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor Physiol Genomics Chiou VL, Burotto M Pseudoprogression and immune-related response in solid tumors.

J Clin Oncol — Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, Brunet I, Wan LX, Rey F, Wang T et al Olfactory receptor responding to gut microbiotaderived signals plays a role in renin secretion and blood pressure regulation.

Proc Natl Acad Sci U S A Jia Q, Xie Y, Lu C, Zhang A, Lu Y, Lv S, Zhang J Endocrine organs of cardiovascular diseases: gut microbiota. J Cell Mol Med — Tang TWH, Chen HC, Chen CY, Yen CYT, Lin CJ, Prajnamitra RP, Chen LL, Ruan SC, Lin JH, Lin PJ et al Loss of gut microbiota alters immune system composition and cripples postinfarction cardiac repair.

Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM et al Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L et al Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis.

Ufnal M, Jazwiec R, Dadlez M, Drapala A, Sikora M, Skrzypecki J Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats. Can J Cardiol Wu H, Kim M, Han J Icariin metabolism by human intestinal microflora.